WO2018005279A1 - Combination chemotherapies - Google Patents
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- WO2018005279A1 WO2018005279A1 PCT/US2017/038964 US2017038964W WO2018005279A1 WO 2018005279 A1 WO2018005279 A1 WO 2018005279A1 US 2017038964 W US2017038964 W US 2017038964W WO 2018005279 A1 WO2018005279 A1 WO 2018005279A1
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- 0 **(C(C=C1*)=O)C(C(C([*-]2*)=C3C(*)=CC2=O)=C)=C1C3=O Chemical compound **(C(C=C1*)=O)C(C(C([*-]2*)=C3C(*)=CC2=O)=C)=C1C3=O 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/131—Amines acyclic
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- Contacting refers to contacting a cell directly or indirectly in vitro, ex vivo, or in vivo (i.e. within a subject, such as a mammal, including humans, mice, rats, rabbits, cats, and dogs). Contacting a ceil, which also includes “reacting" a cell, can occur as a result of administration to a subject. Contacting
- heteroalkyl “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, aikenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other that carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
- aromatic heterocyclic groups are pyridinyl, imidazoiyi, pyrimidinyi, pyrazoly!, triazoiyi, pyrazinyl, tetrazolyi, furyl, thienyi, Isoxazolyl, thiazolyl, oxazolyi, isothiazolyi, pyrrolyl, quinoiiny!, isoquinoliny!, indolyl, benzimidazo!yl, benzofuranyi, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thladiazolyl, furazanyl, benzofurazanyi, benzothiophenyi, benzothiazolyl, benzoxazolyl, quinazo!in
- the foregoing groups may be C-attached or N-attached where such is possible.
- a group derived from pyrrole may be pyrroi-l-yl (N-attached) or pyrroi-3-yl (C-attached).
- a group derived from imidazole may be imidazo!-l-yi or imidazol-3-yl (both N-attached) or imidazol -2-yi, imidazoi-4-yl or imidazol -5-yl (all C- attached).
- the heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo ( ⁇ 0) moieties such as pyrroiidin-2-one.
- a heterocyclyl group ma be optionaliy substituted.
- Heterocycle or “heterocyclic” refers to a monovalent saturated, unsaturated or aromatic (heteroaryi) carbocyciic group having a single ring or multiple condensed rings having at least one hetero atom, such as nitrogen, sulfur or oxygen within the ring, which can optionally be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, alkyl, substituted aikyl, alkoxy, substituted aikoxy, aryl, substituted aryl, halo, mercapto, and other non-interfering substituents,
- a "heterocycioa!kyi” group refers to a cycloa!kyi group that Includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
- the radicals may be fused with an aryl or heteroaryi.
- hydroxy refers to an - ⁇ OH radical.
- alkoxy refers to an— -O- alkyl radical.
- lower alkylmercapto refers to a sulfide group that is substituted with a lower a!kyl group
- lower alkyl sulfonyl refers to a sulfone group that is substituted with a lower alkyl group
- Neoplasm is defined as in Stedmart's Medicai Dictionary 25th Edition (1990) and refers to an abnormal tissue that grows by cellular proliferation more rapidly than normal and continues to grow after the stimuli that initiated the new growth ceases. Neoplasms show partial or complete lack of structural organization and functional coordination compared with normal tissue, and usually form a distinct mass of tissue that may be either benign (benign tumor) or malignant (cancer).
- substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: (Cl ⁇ C6)alkyi, (C2-C6)aikenyl, (C2-C6)aikynyl, (Cl-C6)heteroalkyl, (Cl-C6)ha!oaikyl, (C2- C6)ha!oalkenyl, (C2-C6)haioa!kynyl, (C3-C6)cycioa!kyi, phenyl, (Ci-C6)alkoxy, phenoxy, (Cl- C6)haloalkoxy, amino, (Cl-C6)aiky!amino, (Cl-C6)a!kyithio, pheny!-S- ⁇ , oxo, (Cl ⁇ C6)alkyi, (C2-C6)aikenyl, (C2-C6)aikynyl, (Cl-C6)
- C6)carboxyester (Cl-C6)carboxamido, (CI-C6)acyloxy, H, halogen, CN, N02, H2, N3, NHCH3, N(CH3)2, SH, SCH3, OH, OCH3, OCF3, CHS, CF3, C(0)CH3, C02CH3, C02H, C(0)NH2, pyridinyl, thiophene, furanyl, (CI-C6)carbamate, and (Cl-CS)urea.
- An optionally substituted group may be unsubstituted (e.g.,—-CH2CH3), fully substituted (e.g., ⁇ CF2CF3), monosubstituted (e.g.,— CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., - ⁇ CH2CF3).
- the term "patient” refers to someone who is or has been under the care of a health care provider, including without limitation, doctors, nurses, naturopaths, therapists, chiropractors, and the like, with respect to the disease or condition at issue.
- pharmaceutically acceptable means pharmacologically acceptable to the subject being administered the agent.
- pharmaceutically acceptable may include agents that may have considerable toxicity towards healthy subjects or cel ls as the case may be.
- a "pharmacological composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and/or excipients.
- the purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
- a "physiologically acceptable carrier” refers to a carrier or diluent that does not cause or unacceptable irritation to an organism and does not unacceptab!y abrogate the biological activity and properties of the administered compound.
- cytotoxic oncology agents such term may include agents that may have considerable toxicity towards healthy subjects or cells as the case may be.
- Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxyiic acids; acetyl formyl and benzoyl derivatives of amines; and the like.
- compositions of the com pounds of the invention are prepared by reacting the free acid or base forms of these compounds with a stoichiotretric amount of the appropriate base or acid in water or In an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety.
- the salts can be prepared in situ during the final isolation and purification of such compounds, or separately by reacting the free base or acid functions with a suitable organic acid or base, for example.
- Representative acid addition salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmatate, stearate, !aurate, borate, benzoate, lactate, phosphate, tosy!ate, mesylate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, iactobionate, iauryi sulfate salts and the like.
- Representative alkali and alkaline earth metal salts include the sodiu m, calcium, potassium and magnesium salts.
- a pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound a nd that is not biologically or otherwise undesirable.
- a compou nd of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordi ngly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosuifates, bisu!fates, sulfites, bisulfites, phosphates, monohydrogenphosphates, di hydrogen phosphates, meta phosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acryiates, formates, isobutyrates, caproates, heptanoates, propio!ates, oxalates, maionates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
- the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyi acid, such as glucuronic acid or ga!acturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid,
- an inorganic acid such as hydrochloric
- the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like
- suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium,
- Prodrugs are inactive or lower activity derivatives or variants of bioactive molecules that are designed to become more activate in vivo by a variet of stimuli. The success of the prodrug approach is illustrated by the fact that about 10% of clinical therapeutics are classified as prodrugs. Prodrug strategies may serve to improve the drug- like properties of bioactive molecules Including bioavailability, ceil permeability, and pharmacokinetics.
- the term "subject” is intended to include human and non-human animals.
- exemplary human subjects include a huma n patient having a disorder, e.g., cancer, or a normal subject.
- non-hu man animals includes all vertebrates, e.g., non- mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).
- substituted means that the group in question, e.g., a!kyl group, etc, may bear one or more substituents,
- groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
- the substituted ary! and heteroaryl groups of the invention have one or more hydrogen atoms replaced with a halo, hydroxy, alky!, a!koxy, amino, cyano, carboxy, carba!koxy, nitro or trifiuoromethyl group
- a halo group is a halogen, and includes fluoro, ch!oro, bromo and iodo groups.
- alkoxy refers to an a!kyi group having at least one oxygen substitutent.
- the term carba!koxy refers to groups of the formula— R— C ⁇ 0)0— where R Is an alkyl group.
- "Substituted aikoxy" refers to— O-su stituted aikyi and includes, by way of example, -OCF3, -OCH2 - ⁇ and the like,
- compositions containing the compound(s) of the described herein can be administered for prophylactic and/or therapeutic treatments, In therapeutic applications, the compositions are administered to a patient already suffering from a proliferative disorder or condition (including, but not limited to, cancer), as described above, in an amount sufficient to treat or at impact the symptoms of the proliferative disorder or condition, if not specifically defined herein, an amount adequate to accomplish this Is defined as "therapeutically effective amount or dose.” Amounts effective for this use depends on the severity and course of the proliferative disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician, in prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular proliferative disorder or condition.
- a proliferative disorder or condition including, but not limited to, cancer
- prophyiacticaiiy effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like, It is considered well within the skill of the art for one to determine such therapeutically effective or prophyiacticaiiy effective amounts by routine experimentation (e.g., a dose escalation clinical trial.
- the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
- thioaikoxy or "thioether” refers to an— S-alkyi radical.
- thioaryioxy refers to an— S-aryi radical.
- treat or “treating" a subject having a disorder refers to administering a regimen to the subject, e.g., the administration of a compound or a composition comprising a compound, such that at least one symptom of the disorder is cured, healed, alleviated, relieved, altered, impacted, remedied, ameliorated, or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.
- ureyi refers to the group— N(R)— C(O)— R ' R" where R, R , and R" are independently selected from hydrogen, aikyi, aryi; and where each of R— R , R' — R" , or R— R" taken together can form a cyclic ring system.
- the present invention involves new anti-cancer agents and strategies, particularly those that have fewer toxic side-effects and are efficacious against a broad spectrum of cancers. Thus new fundamental treatment paradigms are required.
- the present invention provides such a break through strategy, compositions and methods.
- the methods described herein can be used with any cancer, for example a carcinoma, a sarcoma, a myeloma, a leukemia, a lymphoma or a mixed type.
- exemplary cancers include leukemia, non-small cell lung cancer, colon cancer, C S cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
- Tumor selectivity is necessary but often not sufficient for ameliorating cancer growth. There is an unmet need for combinations that synergize at the mechanistic level to selectively increase local toxicity locally in the cancer microenvironment, while not increasing genera! toxicity in non-disease tissues.
- ROS levels are relevant for the maintenance of cellular homeostasis in normal cells, but most cancer cells show metabolic alterations resulting in significantly higher ROS levels, which can trigger pro- as well as anti-tumorigenic processes.
- the increased levels of ROS can promote pro-survival and pro-proliferative pathways as well as the metabolic adaption of tumor cells to the tumor environment.
- Lennicke et ai Cell Communication and Signaling (2015) 13:39.
- the instant invention manipulates these natural phenomena in order to promote the anti-tu morigenic potential of ROS.
- Hydrogen peroxide is a key member of the class of reactive oxygen species (ROS), which are byproducts of the cellular metabolism Including protein folding. U nlike the superoxide anion and hydroxy! radical, the less reactive H202 is involved in many physiological processes such as hypoxic signal transduction, cell differentiation and proliferation but also plays a role in mediating immune responses. H202 exerts its effects depending on the cellular context, its local concentration as well as its exposure time. Thus H202 is often considered an unwanted rather toxic byproduct, but plays an important role in the control of vital cellular processes. Lennicke et ai. Cell Communication and Signaling (2015) 13:39, The manipulation of the increased ROS, especially hydrogen peroxide, in tumor cells provides provides the basis for the instant Invention.
- ROS reactive oxygen species
- ROS levels are associated with increased ROS levels.
- increased spatially localized ROS levels promotes cell toxicity thereby leading to the activation of cell cycle arrest or cell death-inducing pathways resulting in the inhibition of cancer progression.
- ⁇ -lapachone and similar analogues can be considered quinone prodrugs according to the present invention.
- Analogues of ⁇ -lapachone useful according to the present invention include those disclosed by US Patents 8,614,228; 8,067,459; 7,812,051; 7,790,765;
- DNQ potently induces death of cancer cells in culture, with IC ⁇ 50) values between 16 and 210 n .
- DNQ is still able to induce cancer cell death under hypoxic conditions.
- DNQ therapeutics provide direct ROS generation as an anticancer strategy. J Am Chem Soc. 2010 Apr 21;132 ⁇ 15):5469-78. doi: 10.1021/jal00610m. Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell Death. Bair JS , Palchaudhuri R, Hergenrother PJ.
- reducing host toxicity is one of the main challenges of cancer chemotherapy.
- Many tumor cells contain high levels of ROS resulting from high levels of the detoxifying enzymes like NQOl, The over expression of these enzymes and resulting over abundance of ROS in tumor cells make them distinctively different from normal cells which do not have high levels of ROS.
- the present invention takes advantage of this phenomenon in a two-pronged synergistic therapeutic strategy: by enhancing the ROS level in tumor cells and by enhancing the cytotoxicity of the ROS using inducers or enhancers of ROS or compounds that activate or are activated by ROS, Examples of compounds according to the present invention that are induced or activated by ROS are certain DMA cross-linking agents disclosed herein.
- quinone-containing molecules are frequently cytotoxic and harm cells through two mechanisms. Many quinones are conjugate addition acceptors and readily alkylate nucleophilic species such as DMA and cysteine residues. Quinones are also substrates for l-e!ectron reductases, such as cytochrome P450s, cytochrome b5, xanthine oxidase, and glutathione reductase.
- quercitin has been shown to increase ROS in leukemia and hepatoma cell lines, curcumin in neuroblastoma, vitamin C in B16 murine cells, and retinoic acid in HL60 cells all leading to apoptosis.
- Chul-Ho Jeong and Sang Hoon Joo Downregulation of Reactive Oxygen Species. Journal of Cancer Prevention Vol. 21, No. 1, 2016.
- an additional type anti-cancer agents are those that are enhanced by ROS, or pro-drugs which get activated or induced by ROS in the cancer microenvironment.
- the selectivity comes from the fact that many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their "healthy” counterparts.
- some cancer cells are hypoxic and have an increase in bioreductive processes, while others have high intracellular concentrations of reactive oxygen species (ROS) due to oxidative stress.
- ROS reactive oxygen species
- pro-drugs that are activated by ROS to become active DNA cross-linking agents that selectively kill cancer cells.
- ROS Modifiers include therapeutically increasing the amount of ROS in cancer cells and simultaneously providing a second compound or compou nds that enhance, induce or activate ROS or compounds that are enhanced, induced or activated by ROS, Such second compounds may be referred to herein without intending any limitation as "ROS Modifiers",
- ROS modifying agents that can be used in conjunction with NQOl substrates or other Producers of ROS include ⁇ -phenethyl isothiocyanate and 2- methoxyoestradiol which have been shown to selectively kill human leukemia cells but not normal lymphocytes by causing further ROS stress in cancer cells.
- ROS modifying agents that can be used in conjunction with NQOl substrates is piper!ongumine and its ana logues which have also found to selectively kill cancer cells by increasing ROS levels but had little effect on primary normal cells.
- a compound of the quinone class any tumor cell growth inhibiting compound which is structurally related to quinone.
- Compounds of the quinone class include, but are not limited to, DNQ and its derivatives as well ⁇ -iapachone and its analogues. Such compou nds also include, but are not limited to, any tumor cell growth inhibiting quinone analog.
- Ros-activated pro-drugs include hydroxyferrocifen (J Med Chem . 2012 Jan
- VELCADE hortezomib
- FOXM1 which inhibits ROS
- overall effect will be an indirect increase ROS.
- Carr JR Wang Z, ogueira V, Hay N, Tyner AL, et al. FoxMl, a critical regulator of oxidative stress during oncogenesis, Embo J. 2009; 28:2908-2918.
- FOX 1 transcriptional activity and expression can also be inhibited by proteasome inhibitors such as bortezomi b (velcade) and MG132, or the thiazole antibiotics, Siomycin and thiostrepton. It was shown that the suppression of FOX 1 by proteasome inhibitors such as bortezomi b (velcade) and MG132, or the thiazole antibiotics, Siomycin and thiostrepton. It was shown that the suppression of FOX 1 by proteasome inhibitors such as bortezomi b (velcade) and MG132, or the thiazole antibiotics, Siomycin and thiostrepton. It was shown that the suppression of FOX 1 by proteasome inhibitors such as bortezomi b (velcade) and MG132, or the thiazole antibiotics, Siomycin and thiostrepton. It was shown that the suppression of FOX 1 by proteasome inhibitors such as bortezomi b (velcade
- proteasome inhibitors sensitizes human cancer cells to cell death induced by D A-damaging agents including doxorubicin and y-irradiation.
- D A-damaging agents including doxorubicin and y-irradiation.
- Thiazole antibiotics target FoxMl and induce apoptosis in human cancer cells.
- mitochondrial electron transport chain modulators e.g., arsenic trioxide
- doxorubicin topoteca n
- redox-cycling compounds e.g., motexafin gadolinium
- agents that disrupt the antioxidant defenses mechanism such as GSH depleting agents (e.g., buthionine sulphoximine, ⁇ -phenyiethyi isothiocyanates (PEITC)) and inhibitors of SOD (e.g., 2- methoxyestradio!), and cataiase (e.g., 3-amino-l,2,4-triazoie).
- GSH depleting agents e.g., buthionine sulphoximine, ⁇ -phenyiethyi isothiocyanates (PEITC)
- PKITC ⁇ -phenyiethyi isothiocyanates
- SOD e.g., 2- methoxyestradio!
- cataiase e.g., 3-amino-l,2,4-triazoi
- compositions described herein for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the active compou nds and one that has no detrimental side effects or toxicity under the conditions of use.
- Such pharmaceutically acceptable excipients preferably include saline (e.g., 0.9% saline), Cremophor EL (which Is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St, Louis, Mo,) (e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanoi), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% t-butanol/60% water).
- polyethylene glycol such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline
- the methods and compositions comprises a NQOl substrate.
- the NQOl substrate is a quinone analog.
- the NQOl substrate comprises DNQ or a DEMQ analogue.
- the NQOl substrate comprises beta lapachone or an analogue thereof.
- the first compound comprises a compound selected from the group consisting of naphtho[2,l-d]oxazo!e-4,5- diones, NPDQ aphtho[l ⁇ ,2':4,5]irnidazo[l,2-a] pyridine-5,6-dione5, beta-lapachone, beta- lapachone analogues, mitomycin C, EQ9, RH1, isothiazolonaphthoquinone aulosirazole, ( ⁇ )- dunnione, and the ortho-quinone of ( ⁇ )-dunnione, Benzofuroxans, Pseudomonas aeruginosa MdaB and WrbA, 2-Substituted 3-methylnaphtho[l,2-b]furan-4,5-diones, tanshinone MA, , Benzofuran-quinones, benzothiophene-
- the at least one second compound is selected from a drug or a pro-drug.
- the pro-drug comprises a compound selected from the group consisting of hydroxyferrocifen, Leinamycin El, [4- (l,3,2-dioxaborinan-2-yl)benzyl ((5-methyl-2-styryl-l,3-dioxan-5-yl)methyl) carbonate], a dual pH-sensitive PBCAE copolymer, a polymeric prodrug of benzoyloxycinnamaldehyde, heme oxygenase-1 inhibiting zinc protoporphyrin micelles, aminoferrocene-based prodrugs, N-benzylaminoferrocene, Thiazolidinone-Based Prodrugs, and INDQ/NO.
- the at least one second compound is selected from ⁇ -phenethyl isothiocyanate, 2- methoxyoestradi
- Ri is alkyl
- R 2 and 4 are each independently - ⁇ X— R;
- each X is independently a direct bond or a bridging group, wherein the bridging group is— 0—,—S-,— H— ,—Ci Oj— ,—Q ⁇ C ⁇ Q ⁇ , -C( Q) ⁇ Q ⁇ ,—O— Ci 0) ⁇ -0- ⁇ , or a linker of the formula— - W--A-W ⁇ -, wherein
- each W is independently— (R')C(-0)— ,— C(-0)N(R)— ,— OC(-O)— ,— C(-0)0— , —0-,— S— ,— S(O)— ,— S(0) 2 — ,— (R')— ,— C(-0)—,— (CH 2 )n— where n is 1-10, or a direct bond, wherein each R' is independently H, (Cl-C6)alkyl, or a nitrogen protecting group; and
- the above composition wherein R 4 is a (Ci- 2o)a!kyi group, in stiii further aspects, the above composition wherein Rs is methyl, in yet other aspects, the above composition wherein f1 ⁇ 2 is methyl. In further aspects, the above composition wherein Ri a rtd R ⁇ are both methyl. In other aspects, the above composition wherein 4 is methyl.
- compositions comprising a compound having the formula:
- each R 1 is independently— B(XR')2, wherein each X is independently selected from 0 and S, and each R' is independently selected from hydrogen and alkyl, or two R' are taken together to form an optionally substituted 5- to 8-membered ring;
- each R 2 is independently selected from optionally substituted alkyi, a!koxy, amino, halo, and -CH 2 -N(R a h®;
- each Y is independently a bond or— CH 2 — ;
- each R !> is independently C1-C alkyS
- each R 3 is independently selected from optionally substituted alkyl
- compositions comprising a com having the formula:
- Ri is aiky!
- R2and R4 are each independently— -X-— R;
- each W is independently— ⁇ R')C(--0)--, --C ⁇ --O)N(R)--,— OC( 0)TM,— C ⁇ 0)0—.. — O— ,—5—,— S(O)— ,— S(0) 2 — ,— N(R')— ,— C(-O)—,— (CH 2 )n— where n is 1-10, or a direct bond, wherein each R' is independently H, (Cl-C6)a!kyl, or a nitrogen protecting group; and
- each A is independently (Ci-C2o)aikyi, ⁇ C?. ⁇ Cis)alkenyl, (C2-Ci6)aikynyl, ⁇ C3- Cg)cycloalkyl, ⁇ C6-Cio)ary!, - ⁇ (OCH 2 - ⁇ CH2)n' ⁇ - where n is 1 to about 20,—
- alkyi or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups;
- X and Y are independently selected from CL and Br and R is independently selected from 2,3-dimethy!butane and H;
- compositions comprising a synergistic effective amount of a NQOl substrate, a synergistic effective amount of an ROS inducible cytotoxin, and a pharmaceutically accepta ble carrier or diluent.
- compositions wherein the second compound is a DNA cross-linking agent.
- the second compound is selected from an aromatic nitrogen mustard, ⁇ -phenethyl isothiocyanate, 2-methoxyoestradiol, and piperiongumine.
- Cancer types may be selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
- the methods and compositions of the invention provide treatment of cancer characterized by tumor cells with elevated NQOl levels comprising administering to a patient affected by such cancer a therapeutically effective amount of one or more compositions of the invention.
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Abstract
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KR1020197002717A KR20190025646A (en) | 2016-06-27 | 2017-06-23 | Combination Chemotherapy |
EP17820974.8A EP3558317A4 (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapies |
MX2018016332A MX2018016332A (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapies. |
AU2017291411A AU2017291411A1 (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapies |
CN201780039807.8A CN109689060A (en) | 2016-06-27 | 2017-06-23 | Chemical treating composition |
US16/313,013 US20200179417A1 (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapies |
BR112018076639-9A BR112018076639A2 (en) | 2016-06-27 | 2017-06-23 | combination chemotherapies |
CA3029228A CA3029228A1 (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapies |
EA201892834A EA201892834A1 (en) | 2016-06-27 | 2017-06-23 | COMBINED CHEMOTHERAPY |
JP2019519611A JP2019518795A (en) | 2016-06-27 | 2017-06-23 | Combination chemotherapy |
IL263785A IL263785A (en) | 2016-06-27 | 2018-12-18 | Combination chemotherapies |
ZA2018/08608A ZA201808608B (en) | 2016-06-27 | 2018-12-20 | Combination chemotherapies |
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US (1) | US20200179417A1 (en) |
EP (1) | EP3558317A4 (en) |
JP (1) | JP2019518795A (en) |
KR (1) | KR20190025646A (en) |
CN (1) | CN109689060A (en) |
AU (1) | AU2017291411A1 (en) |
BR (1) | BR112018076639A2 (en) |
CA (1) | CA3029228A1 (en) |
EA (1) | EA201892834A1 (en) |
IL (1) | IL263785A (en) |
MX (1) | MX2018016332A (en) |
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Cited By (3)
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WO2019198976A1 (en) * | 2018-04-09 | 2019-10-17 | 주식회사 휴엔 | Pharmaceutical composition comprising derivative compound of 1,2-naphthoquinone for preventing or treating solid cancer or blood cancer |
WO2019198977A1 (en) * | 2018-04-09 | 2019-10-17 | 영진약품 주식회사 | Pharmaceutical composition including 1,2-naphthoquinone derivative compound for prevention or treatment of solid cancers or blood cancers |
WO2020246807A3 (en) * | 2019-06-04 | 2021-01-21 | 주식회사 엘마이토테라퓨틱스 | Pharmaceutical composition for treating cancer, containing naphthoquinone compound |
Families Citing this family (5)
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JP7267194B2 (en) * | 2017-05-15 | 2023-05-01 | 浜松ホトニクス株式会社 | catheter kit |
KR102591933B1 (en) * | 2020-02-14 | 2023-10-23 | 사회복지법인 삼성생명공익재단 | Pharmaceutical composition for preventing or treating cancer comprising genipin and elesclomol |
TWI832069B (en) * | 2020-07-10 | 2024-02-11 | 南韓商娜迪安生物公司 | Pharmaceutical composition which is for preventing or treating cancer and contains naphthoquinone-based compound and immune checkpoint inhibitor as active ingredient |
CN111965354A (en) * | 2020-07-27 | 2020-11-20 | 温州医科大学 | Application of HO-1 protein in breast cancer prognosis evaluation kit and diagnosis kit |
CN112516310B (en) * | 2020-12-11 | 2022-11-29 | 武汉理工大学 | Preparation method and application of nano prodrug with response to tumor acid environment |
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EP3560497A1 (en) * | 2012-08-30 | 2019-10-30 | The Texas A&M University System | Compositions and methods for drug-sensitization or inhibition of a cancer cell |
-
2017
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- 2017-06-23 WO PCT/US2017/038964 patent/WO2018005279A1/en unknown
- 2017-06-23 BR BR112018076639-9A patent/BR112018076639A2/en not_active Application Discontinuation
- 2017-06-23 KR KR1020197002717A patent/KR20190025646A/en unknown
- 2017-06-23 US US16/313,013 patent/US20200179417A1/en not_active Abandoned
- 2017-06-23 JP JP2019519611A patent/JP2019518795A/en active Pending
- 2017-06-23 EP EP17820974.8A patent/EP3558317A4/en not_active Withdrawn
- 2017-06-23 AU AU2017291411A patent/AU2017291411A1/en not_active Abandoned
- 2017-06-23 CA CA3029228A patent/CA3029228A1/en not_active Abandoned
- 2017-06-23 EA EA201892834A patent/EA201892834A1/en unknown
- 2017-06-23 CN CN201780039807.8A patent/CN109689060A/en active Pending
-
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- 2018-12-18 IL IL263785A patent/IL263785A/en unknown
- 2018-12-20 ZA ZA2018/08608A patent/ZA201808608B/en unknown
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2019198976A1 (en) * | 2018-04-09 | 2019-10-17 | 주식회사 휴엔 | Pharmaceutical composition comprising derivative compound of 1,2-naphthoquinone for preventing or treating solid cancer or blood cancer |
WO2019198977A1 (en) * | 2018-04-09 | 2019-10-17 | 영진약품 주식회사 | Pharmaceutical composition including 1,2-naphthoquinone derivative compound for prevention or treatment of solid cancers or blood cancers |
CN112118840A (en) * | 2018-04-09 | 2020-12-22 | 永进药品工业株式会社 | Pharmaceutical composition for preventing or treating solid cancer or leukemia comprising 1, 2-naphthoquinone derivative compound |
JP2021523095A (en) * | 2018-04-09 | 2021-09-02 | ユンジン ファーム.カンパニー、リミテッド | A pharmaceutical composition for the prevention or treatment of solid or hematological cancers containing a 1,2-naphthoquinone derivative compound. |
US11684610B2 (en) | 2018-04-09 | 2023-06-27 | Yungjin Pharm. Co., Ltd. | Pharmaceutical composition including 1,2-naphthoquinone derivative compound for prevention or treatment of solid cancers or blood cancers |
US11717511B2 (en) | 2018-04-09 | 2023-08-08 | Huen Co., Ltd. | Pharmaceutical composition comprising derivative compound of 1,2-naphthoquinone for preventing or treating solid cancer or blood cancer |
JP7447013B2 (en) | 2018-04-09 | 2024-03-11 | ユンジン ファーム.カンパニー、リミテッド | Pharmaceutical composition for preventing or treating solid cancer or blood cancer containing a 1,2-naphthoquinone derivative compound |
CN112118840B (en) * | 2018-04-09 | 2024-05-07 | 永进药品工业株式会社 | Pharmaceutical composition comprising 1, 2-naphthoquinone derivative compound for preventing or treating solid cancer or leukemia |
WO2020246807A3 (en) * | 2019-06-04 | 2021-01-21 | 주식회사 엘마이토테라퓨틱스 | Pharmaceutical composition for treating cancer, containing naphthoquinone compound |
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EA201892834A1 (en) | 2019-07-31 |
CA3029228A1 (en) | 2018-01-04 |
MX2018016332A (en) | 2019-11-28 |
ZA201808608B (en) | 2019-06-26 |
KR20190025646A (en) | 2019-03-11 |
US20200179417A1 (en) | 2020-06-11 |
JP2019518795A (en) | 2019-07-04 |
EP3558317A1 (en) | 2019-10-30 |
CN109689060A (en) | 2019-04-26 |
BR112018076639A2 (en) | 2019-04-02 |
IL263785A (en) | 2019-01-31 |
AU2017291411A1 (en) | 2019-01-03 |
EP3558317A4 (en) | 2020-03-18 |
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